This is a new 3-year R01 application involving a NCI/CTEP awarded phase II study that will evaluate the ability of the MEK 1/2 inhibitor trametinib (GlaxoSmithKline, GSK1120212) to restore radioiodine (RAI) incorporation and efficacy for patients with RAS mutant (MUT) or BRAF/RAS wild-type (WT), RAI-refractory (RAIR) thyroid cancers. This trial will be conducted as a multicenter study with MSKCC as the lead center and the NIH a collaborating site. Metastatic disease represents the most frequent cause of thyroid cancer-related death, and RAI (or 131I) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and are hence refractory to RAI, heralding a poor prognosis. Papillary thyroid cancers (PTC) are associated with mutually exclusive mutations of oncogenes encoding effectors of the mitogen activated protein kinase (MAPK) signaling pathway (i.e. RET, NTRK, RAS and BRAF). Oncogenic activation of MAPK signaling in thyroid cells contributes to RAI refractoriness by suppressing the expression of genes required for iodine uptake and retention. In mouse models of thyroid cancer, we discovered that pharmacologic inhibition of the MAPK pathway restored the expression of these genes and the ability of tumors to trap RAI. Based on these observations, we conducted a pilot clinical trial which demonstrated that the MEK inhibitor selumetinib (AstraZeneca) can restore RAI efficacy in a subset of RAIR patients. 124I PET/CT scans were used to quantify selumetinib-induced changes in iodine incorporation within individual thyroid tumors and predict the clinical efficacy of therapeutic 131I, an innovative analytic technique termed lesional dosimetry. This approach was particularly effective for RAS MUT cancers; more heterogeneous results were observed for BRAF/RAS WT tumors. What is now required is a proof-of-concept, genotype-focused clinical trial to determine if this is a clinically effective targeted approach for treating RAS MUT disease, and explore the hypothesis that more potent MEK inhibition can optimize RAI efficacy for BRAF/RAS WT patients. With the central hypothesis that maximal MEK inhibition is required to optimally restore RAI efficacy for RAS MUT and BRAF/RAS WT RAIR thyroid cancer patients, we propose to conduct a clinical trial using the more potent MEK inhibitor trametinib to restore RAI incorporation (measured by 124I PET lesional dosimetry) and efficacy in these patients (AIM #1). We will also perform correlative tissue studies to determine how the genomic landscape and trametinib-induced changes in gene expression correlate to the clinical impact of the drug upon RAI action within tumors (AIM #2). Using a targeted therapy to restore RAI efficacy, conducting 124I PET lesional dosimetry to guide clinical use of RAI, and developing a novel targeted approach for treating RAS MUT disease represent paradigm-shifting advances for the treatment of RAIR thyroid cancers that could also hold implications for other cancers in which re-differentiation concepts may be explored as novel therapies.